FDA Modifies cGMP Guide - New Text Published

GMP News
13 December 2007

FDA Modifies cGMP Guide  New Text Published

On 4 December 2007 the US Food & Drug Administration (FDA) has published changes
to the cGMP Guide. We already reported about the planned measures in our
News
from 25 October 2007. They were also presented by Fred Blumenschein from the
authority on the occasion of the 2nd European GMP Conference end of June in
Heidelberg, Germany, which was organised by the ECA and the European QP
Association.

With the announcement of the new text the FDA also withdrew the "proposed rule"
from 1996. This proposed rule contained major modifications of the cGMP Guide.
However, a FDA working group found out, that the planned changes are not
compliant with the authority's new risk based approach for the 21st Century any
more.

On the one hand the FDA intends to substantiate certain requirements with the
changes. On the other hand it wants to accomplish an incremental approach to
modernisation of cGMP. The modified guide is then supposed to comply with the
FDA initiative for the 21st Century.

For instance, one change affects the area "Aseptic Processing". With this regard
the FDA has published the Guidance for Industry "Sterile Drug Products Produced
by Aseptic Processing" in September 2004. This document was developed following
an analysis of the GMP Harmonisation Analysis Working Group. One part of the
analysis was a comparison with the EC GMP Guide. Now the FDA has implemented the
necessary concretion in the cGMP Guide and has matched it more to the September
2004 Guidance. The new text is not surprising, because it mainly contains
requirements that have been interpretations of the authority for several years.
However, now the FDA also established the legal scope.

The changes listed below become effective on 17 April 2008. Comments can be
provided until 19 February 2008. If there are no essential comments that will
prevent the authority from implementing the new content, the FDA will issue an
announcement in the Federal Register on 18 March 2008 which will confirm the
mentioned due date.

Following you'll fin the new texts:

PART 210-CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING,
PACKING, OR HOLDING OF DRUGS; GENERAL

■ 2. Section 210.3 is amended by revising paragraph (b)(6) to read as follows:
§ 210.3 Definitions.
(b) * * *
(6) Nonfiber releasing filter means any filter, which after appropriate
pretreatment such as washing or flushing, will not release fibers into the
component or drug product that is being filtered. * * * * *

PART 211-CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS

■ 4. Section 211.48 is amended by revising paragraph (a) to read as follows: § 211.48 Plumbing.
(a)
Water supplied by the plumbing system of the facility must be safe for human
consumption. This water shall be supplied under continuous positive pressure in
a plumbing system free of defects that could contribute contamination to any
drug product.
* * * *

■ 5. Section 211.67 is amended by revising paragraph (a) to read as follows: § 211.67 Equipment cleaning and maintenance. (a)
Equipment and utensils shall be cleaned, maintained, and sanitized and/ or
sterilized at appropriate intervals to prevent malfunctions or contamination
that would alter the safety, identity, strength, quality, or purity of the drug
product beyond the official or other established requirements.
* * * * *

■ 6. Section 211.68 is amended by adding paragraph (c) to read as follows: § 211.68 Automatic, mechanical, and electronic equipment.
* * * * *
(c)
Such automated equipment used for performance of operations addressed by §§
211.101(c) or (d), 211.103, 211.182, or 211.188(b)(11) can satisfy the
requirements included in those sections for the performance of an operation by
one person and checking by another person if such equipment is used in
conformity with this section and one person verifies that the operations
addressed in those sections are performed accurately by such equipment.

■ 7. Section 211.72 is revised to read as follows: § 211.72 Filters.
Filters for liquid filtration used in the manufacture, processing, or packing of
injectable drug products intended for human use shall not release fibers into
such products. Fiber-releasing filters may not be used in the manufacture,
processing, or packing of these injectable drug products unless it is not
possible to manufacture such drug products without the use of such filters. If
use of a fiber-releasing filter is necessary, an additional nonfiber-releasing
filter of 0.22 micron maximum mean porosity (0.45 micron if the manufacturing
conditions so dictate) shall subsequently be used to reduce the content of
particles in the injectable drug product.

■ 8. Section 211.82 is amended by revising paragraph (b) to read as follows: § 211.82 Receipt and storage of untested components, drug product containers,
and closures.
* * * *
(b)
Components, drug product containers, and closures shall be stored under
quarantine until they have been tested or examined, whichever is appropriate,
and released. Storage within the area shall conform to the requirements of §
211.80.

■ 9. Section 211.84 is amended by revising paragraphs (c)(1), (d)(3), and (d)(6)
to read as follows: § 211.84 Testing and approval or rejection of components, drug product
containers, and closures.
* * * * *
(c)
* * *
(1)
The containers of components selected shall be cleaned when necessary in a
manner to prevent introduction of contaminants into the component.
* * * * *
(d)
* * *
(3) Containers and closures shall be tested for conformity with all appropriate
written specifications. In lieu of such testing by the manufacturer, a
certificate of testing may be accepted from the supplier, provided that at least
a visual identification is conducted on such containers/closures by the
manufacturer and provided that the manufacturer establishes the reliability of
the supplier's test results through appropriate validation of the supplier's
test results at appropriate intervals.
* * * * *
(6) Each lot of a component, drug product container, or closure with potential
for microbiological contamination that is objectionable in view of its intended
use shall be subjected to microbiological tests before use.
* * * * *

■ 10. Section 211.94 is amended by revising paragraph (c) to read as follows:
§ 211.94 Drug product containers and closures.
* * * * *
(c)
Drug product containers and closures shall be clean and, where indicated by the
nature of the drug, sterilized and processed to remove pyrogenic properties to
assure that they are suitable for their intended use. Such depyrogenation
processes shall be validated.
* * * *

■ 11. Section 211.101 is amended by revising paragraphs (c) and (d) to read as
follows: § 211.101 Charge-in of components.
*
* * * *
(c)
Weighing, measuring, or subdividing operations for components shall be
adequately supervised. Each container of component dispensed to manufacturing
shall be examined by a second person to assure that:
(1)
The component was released by the quality control unit;
(2)
The weight or measure is correct as stated in the batch production records;
(3)
The containers are properly identified. If the weighing, measuring, or
subdividing operations are performed by automated equipment under § 211.68, only
one person is needed to assure conditions of paragraphs (c)(1), (c)(2), and
(c)(3) of this section have been met.
(d)
Each component shall either be added to the batch by one person and verified by
a second person or, if the components are added by automated equipment under §
211.68, only verified by one person.

■ 12. Section 211.103 is revised to read as follows: § 211.103 Calculation of yield.
Actual yields and percentages of theoretical yield shall be determined at the
conclusion of each appropriate phase of manufacturing, processing, packaging, or
holding of the drug product. Such calculations shall either be performed by one
person and independently verified by a second person, or, if the yield is
calculated by automated equipment under § 211.68, be independently verified by
one person.

■ 13. Section 211.110 is amended by revising paragraph (a) introductory text and
by adding paragraph (a)(6) to read as follows: § 211.110 Sampling and testing of in-process materials and drug products.
(a)
To assure batch uniformity and integrity of drug products, written procedures
shall be established and followed that describe the in-process controls, and
tests, or examinations to be conducted on appropriate samples of in-process
materials of each batch. Such control procedures shall be established to monitor
the output and to validate the performance of those manufacturing processes that
may be responsible for causing variability in the characteristics of in-process
material and the drug product. Such control procedures shall include, but are
not limited to, the following, where appropriate:
*
* * * *
(6) Bioburden testing. * * * * *

■ 14. Section 211.113 is amended by revising paragraph (b) to read as follows:
§ 211.113 Control of microbiological contamination.
*
* * * *
(b)
Appropriate written procedures, designed to prevent microbiological
contamination of drug products purporting to be sterile, shall be established
and followed. Such procedures shall include validation of all aseptic and
sterilization processes.

■ 15. Section 211.160 is amended by revising paragraph (b)(1) to read as
follows: 211.160 General requirements.
* * * * *
(b)
* * *
(1)
Determination of conformity to applicable written specifications for the
acceptance of each lot within each shipment of components, drug product
containers, closures, and labeling used in the manufacture, processing, packing,
or holding of drug products. The specifications shall include a description of
the sampling and testing procedures used. Samples shall be representative and
adequately identified. Such procedures shall also require appropriate retesting
of any component, drug product container, or closure that is subject to
deterioration.
* * * * *

■ 16. Section 211.182 is revised to read as follows: § 211.182 Equipment cleaning and use log.
A written record of major equipment cleaning, maintenance (except routine
maintenance such as lubrication and adjustments), and use shall be included in
individual equipment logs that show the date, time, product, and lot number of
each batch processed. If equipment is dedicated to manufacture of one product,
then individual equipment logs are not required, provided that lots or batches
of such product follow in numerical order and are manufactured in numerical
sequence. In cases where dedicated equipment is employed, the records of
cleaning, maintenance, and use shall be part of the batch record. The persons
performing and double-checking the cleaning and maintenance (or, if the cleaning
and maintenance is performed using automated equipment under § 211.68, only the
person verifying the cleaning and maintenance done by the automated equipment)
shall date and sign or initial the log indicating that the work was performed.
Entries in the log shall be in chronological order.

■ 17. Section 211.188 is amended by revising paragraph (b)(11) to read as
follows:§ 211.188 Batch production and control records.
* * * * *
(b) * * *
(11) Identification of the persons performing and directly supervising or
checking each significant step in the operation, or if a significant step in the
operation is performed by automated equipment under § 211.68, the identification
of the person checking the significant step performed by the automated
equipment.
* * * * *

Prepared by:
Oliver Schmidt
On behalf of the European Compliance Academy (ECA)